Applying logic to pulmonary artery catheter use

Mansour and colleagues recommend not routinely using the pulmonary artery catheter to guide hemodynamic management in the intensive care unit, because the perceived benefits are largely intangible [1]. Pulmonary artery catheter monitoring of the right ventricular ejection fraction (RVef) and of the right ventricular end-diastolic volume (EDV), however, reflects powerful yet underutilized relationships that assess right ventricular performance. Since the cardiac output equals the product of the RVef, the EDV and the heart rate, one can assess the RVef to EDV relations as direct measures of right ventricular performance. A series of RVef, EDV and heart rate combinations can give the same cardiac output (Figure 1); monitoring or targeting cardiac output alone ignores this reality. For example, in hypovolemia the EDV is low and the RVef is increased

Isocyanide Multicomponent Reactions on Solid-Phase-Coupled DNA Oligonucleotides for Encoded Library Synthesis

Isocyanide multicomponent reactions play a prominent role in drug discovery. This chemistry has hardly been investigated for compatibility with DNA-encoded combinatorial synthesis. The Ugi, Ugi-azide, and Groebke-Blackburn-Bienaymé reactions are well-tolerated by DNA on the solid phase and show a broad scope. However, an oxadiazole-forming variant of the Ugi reaction caused DNA depurination, requiring a more stable hexathymidine DNA for encoded library synthesis. Cheminformatic analysis revealed that isocyanide multicomponent-reaction-based encoded libraries cover a diverse chemical space

Longitudinal measures of lung function in infants with bronchopulmonary dysplasia

We previously demonstrated that infants with a history of bronchopulmonary dysplasia (BPD) exhibit airflow obstruction and air trapping. The purpose of this study was to assess longitudinal changes in pulmonary function in infants with a history of BPD over the first 3 years of life, and the relationship to somatic growth. Spirometry was measured using the raised volume rapid thoracoabdominal compression technique, and lung volumes measured by plethysmography. Eighteen infants (mean gestational age ± SD 27.3 ± 2.2 weeks, birthweight 971 ± 259 g) underwent two lung function studies. Average age at first test was 58.8 weeks. Spirometry demonstrated significant reductions in forced expiratory volume in 0.5 sec (FEV 0.5 , 76.0 ± 15.9% predicted, Z-score −2.13 ± 1.69), forced expiratory flow at 75% of expired forced vital capacity (FEF 75 , 54.8 ± 31.1%, −3.58 ± 2.73), and FEF 25–75 (67.8 ± 33.3%, −1.79 ± 1.76). Group mean total lung capacity (TLC) was in the low normal range (82.9 ± 13.5% predicted) and residual volume (RV)/TLC was mildly elevated (122.4 ± 38.2% predicted). Repeat testing was performed an average of 32.7 weeks after initial testing. At re-evaluation, group mean lung volumes and flows tracked at or near their previous values; thus, in general, there was a lack of catch-up growth. However, compared to infants with below average or average somatic growth (as represented by g/day), infants with above average growth showed significantly greater improvements in percent predicted FVC, FEV 0.5 , TLC, and RV/TLC (all P  < 0.05, ANOVA). We conclude that longitudinal measures of pulmonary function in infants and young children with BPD demonstrate significant airflow obstruction and modest restriction, which tends to persist with time. On the other hand, infants with above average somatic growth showed greater lung growth than their peers. Additional studies examining the effects of various nutritional regimens on lung function are warranted. Pediatr Pulmonol. 2011; 46:369–375. © 2010 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/83461/1/21378_ftp.pd

Sildenafil attenuates pulmonary inflammation and fibrin deposition, mortality and right ventricular hypertrophy in neonatal hyperoxic lung injury

<p>Abstract</p> <p>Background</p> <p>Phosphodiesterase-5 inhibition with sildenafil has been used to treat severe pulmonary hypertension and bronchopulmonary dysplasia (BPD), a chronic lung disease in very preterm infants who were mechanically ventilated for respiratory distress syndrome.</p> <p>Methods</p> <p>Sildenafil treatment was investigated in 2 models of experimental BPD: a lethal neonatal model, in which rat pups were continuously exposed to hyperoxia and treated daily with sildenafil (50–150 mg/kg body weight/day; injected subcutaneously) and a neonatal lung injury-recovery model in which rat pups were exposed to hyperoxia for 9 days, followed by 9 days of recovery in room air and started sildenafil treatment on day 6 of hyperoxia exposure. Parameters investigated include survival, histopathology, fibrin deposition, alveolar vascular leakage, right ventricular hypertrophy, and differential mRNA expression in lung and heart tissue.</p> <p>Results</p> <p>Prophylactic treatment with an optimal dose of sildenafil (2 × 50 mg/kg/day) significantly increased lung cGMP levels, prolonged median survival, reduced fibrin deposition, total protein content in bronchoalveolar lavage fluid, inflammation and septum thickness. Treatment with sildenafil partially corrected the differential mRNA expression of amphiregulin, plasminogen activator inhibitor-1, fibroblast growth factor receptor-4 and vascular endothelial growth factor receptor-2 in the lung and of brain and c-type natriuretic peptides and the natriuretic peptide receptors NPR-A, -B, and -C in the right ventricle. In the lethal and injury-recovery model we demonstrated improved alveolarization and angiogenesis by attenuating mean linear intercept and arteriolar wall thickness and increasing pulmonary blood vessel density, and right ventricular hypertrophy (RVH).</p> <p>Conclusion</p> <p>Sildenafil treatment, started simultaneously with exposure to hyperoxia after birth, prolongs survival, increases pulmonary cGMP levels, reduces the pulmonary inflammatory response, fibrin deposition and RVH, and stimulates alveolarization. Initiation of sildenafil treatment after hyperoxic lung injury and continued during room air recovery improves alveolarization and restores pulmonary angiogenesis and RVH in experimental BPD.</p

TEAD-YAP Interaction Inhibitors and MDM2 Binders from DNA-Encoded Indole-Focused Ugi Peptidomimetics

DNA-encoded combinatorial synthesis provides efficient and dense coverage of chemical space around privileged molecular structures. The indole side chain of tryptophan plays a prominent role in key, or “hot spot”, regions of protein–protein interactions. A DNA-encoded combinatorial peptoid library was designed based on the Ugi four-component reaction by employing tryptophan-mimetic indole side chains to probe the surface of target proteins. Several peptoids were synthesized on a chemically stable hexathymidine adapter oligonucleotide “hexT”, encoded by DNA sequences, and substituted by azide-alkyne cycloaddition to yield a library of 8112 molecules. Selection experiments for the tumor-relevant proteins MDM2 and TEAD4 yielded MDM2 binders and a novel class of TEAD-YAP interaction inhibitors that perturbed the expression of a gene under the control of these Hippo pathway effectors

Motivational modulation of bradykinesia in Parkinson's disease off and on dopaminergic medication.

Motivational influence on bradykinesia in Parkinson's disease may be observed in situations of emotional and physical stress, a phenomenon known as paradoxical kinesis. However, little is known about motivational modulation of movement speed beyond these extreme circumstances. In particular, it is not known if motivational factors affect movement speed by improving movement preparation/initiation or execution (or both) and how this effect relates to the patients' medication state. In the present study, we tested if provision of motivational incentive through monetary reward would speed-up movement initiation and/or execution in Parkinson's disease patients and if this effect depended on dopaminergic medication. We studied the effect of monetary incentive on simple reaction time in 11 Parkinson's disease patients both "off" and "on" dopaminergic medication and in 11 healthy participants. The simple reaction time task was performed across unrewarded and rewarded blocks. The initiation time and movement time were quantified separately. Anticipation errors and long responses were also recorded. The prospect of reward improved initiation times in Parkinson's disease patients both "off" and "on" dopaminergic medication, to a similar extent as in healthy participants. However, for "off" medication, this improvement was associated with increased frequency of anticipation errors, which were eliminated by dopamine replacement. Dopamine replacement had an additional, albeit small effect, on reward-related improvement of movement execution. Motivational strategies are helpful in overcoming bradykinesia in Parkinson's disease. Motivational factors may have a greater effect on bradykinesia when patients are "on" medication, as dopamine appears to be required for overcoming speed-accuracy trade-off and for improvement of movement execution. Thus, medication status should be an important consideration in movement rehabilitation programmes for patients with Parkinson's disease